The Clinical Utility of Tumour Mutational Signatures for Identifying Hereditary Colorectal Cancer and Polyposis syndromes

Peter Georgeson1,2, Khalid Mahmood1,2,3, Bernard Pope1,2,3, Mark Clendenning1,2, Abi Ragunathan1,2, Romy Walker1,2, Jihoon Joo1,2, Harindra Jayasekara1,2, Ryan Hutchinson1,2, Christophe Rosty1,2,4, Finlay Macrae5,6,7, John Hopper8,2, Mark Jenkins8,2, Ingrid Winship5,6, Daniel Buchanan1,2,5

1Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Australia. 2University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Australia. 3Melbourne Bioinformatics, The University of Melbourne, Parkville, Australia. 4Envoi Pathology, Brisbane, Australia. 5Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Australia. 6Department of Medicine, The University of Melbourne, Parkville, Australia. 7Colorectal Medicine and Genetics, Royal Melbourne Hospital, Parkville, Australia. 8Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Australia


Objectives: Tumour mutational signatures (TMS) provide insights into tumour aetiology.  TMS have been identified that relate to mismatch repair (MMR; signatures SBS6, SBS15, SBS20, SBS26), POLE exonuclease domain mutations (SBS10, SBS14), and base excision repair (BER) defects in NTHL1 (SBS30) and MUTYH (SBS18, SBS36).  The aim of this study was to assess the utility of TMS in colorectal cancers (CRCs) and adenomas for identifying pathogenic variant carriers in genes underlying hereditary CRC and polyposis syndromes.

Methods: CRC and adenoma FFPE tissue from germline carriers in the MMR genes, MUTYH, NTHL1, POLE, POLD1, BRCA1, AXIN2 and RNF43 genes were tested using whole exome sequencing and compared with 18 sporadic CRCs.  We calculated TMS for each tumour using the 95 defined COSMIC signatures (version 3) and assessed their ability to differentiate carriers from non-carriers.

Results:  SBS36 was dominant in MUTYH biallelic carriers, but absent in a monoallelic carrier and a compound heterozygote with a variant of uncertain significance (VUS), suggesting it is not pathogenic.  SBS30 was dominant in a biallelic NTHL1 carrier but absent in four monoallelic carriers.  CRCs from 10 MLH1, 4 MSH2 and 4 MSH6 carriers (Lynch syndrome) exhibited dominant SBS6.  SBS6 in these carriers were not ostensibly different to 8 MLH1 methylated or 10 sporadic MMR-proficient CRCs. A CRC from a BRCA1 mutation carrier demonstrated SBS39.

Conclusions: The dominant TMS observed in CRCs and adenomas in hereditary syndromes were consistent with the underlying germline defect and showed utility for discriminating from sporadic CRCs, and for classifying a MUTYH VUS.